The long-term goal of this work is to rationally manipulate G protein-coupled receptor (GPCRs) activation with the hope to develop novel therapeutic approaches in this major family of transmembrane receptors and drug targets. Our hypothesis is that evolutionary patterns of amino acid substitutions can reveal sequence positions that play major roles across GPCRs, individually or together, in order to mediate ligand binding, conformation switching, and finally ligand-biased activation of efferent signaling pathways that can be G protein-dependent or -independent. In the past funding period, computational analysis identified such evolutionary patterns and revealed: allosteric switches that in D2-type dopamine receptors (D2R) rewire signaling from dopamine to serotonin, or, that selectively block downstream G protein-dependent or -independent signaling. We also found other switches that separated ligand binding from receptor signaling in the extracellular domain of metabotropic glutamate receptors (MGluR). Technical progress also led to increased accuracy as a result of insuring computational similarity among structural neighbor residues, and for the first time linking our algorithms to a first-principle equation for the evolutionary variations of genotype and phenotype. Together these data and other data support new, twinned biological and algorithmic aims: 1. To redirect ligand binding in bioamine receptors. 2. To redesign ligand binding and dimerization in metabotropic glutamate receptors. 3. To identify the components of the allosteric pathway extending from the ligand binding site to the G protein-coupled interfaces. The outcome should reveal new aspects of the molecular basis of signaling in an important family of pharmaceutical targets. It will also link sequence and structure genomics databases to the molecular basis of function and to the rational re-design of protein interactions-key steps towards manipulating cellular pathways.